Mechanisms of transcription termination

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Understanding the molecular mechanisms governing the expression of genes is an essential part of developing strategies for intelligent manipulation of harmful and useful organisms, development of new antimicrobial and antifungal agents, fighting diseases, and, importantly, for understanding emergence and evolution of Life.In all living organisms the first step of gene expression is accomplished by highly conserved multi-subunit RNA polymerases (RNAPs). Termination is an essential step of transcription that ensures recycling of RNAP and proper expression of neighbouring genes. However, the mechanisms of termination remain poorly understood.Recently we discovered an elegant scenario of termination by RNA polymerase III, which transcribes many essential genes in eukaryotic cell. We discovered analogies with bacterial termination, which suggest that this fundamental mechanism have emerged billions years ago, before divergence of three domains of life. This research inspired us to investigate the mechanisms of termination by RNA polymerase I, which synthesises most of RNA in eukaryotic cell, and Archaeal RNAP, which functions in the third, much understudied, domain of life. Malfunctions in RNA polymerase I is linked with diseases such as cancer, Alzheimer's and others. Archaea are important players in ecology and biotechnology, as well as inhabit humans and ruminant's guts. Therefore besides fundamental importance, the proposed study may have an impact on medical and environmental research, agriculture and biotechnology. Also, as suggested by our findings with RNA polymerase III, the study may reveal new and/or unique features of these RNA polymerases as well as improve understanding of evolutionary relations among the mechanisms of multi-subunit RNAPs' functioning. The wide range of techniques required to achieve these aims have uniquely accumulated through years in our lab, and for example allowed us to decipher mechanism of termination by RNA polymerase III, describe a mechanism involved in regulation of the development of HIV-1, and to uncover mode of action of antibiotic Tagetitoxin. The proposed research will add to these techniques and will provide new tools for investigation of the first step of gene expression as well as for design and testing of novel drugs.